Abstract
BackgroundChemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague.MethodsThe efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed.ResultsChemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC.ConclusionsThese studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.
Highlights
Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses
We proved interference with ATP-binding cassette transporter G1 (ABCG1) expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC
ABCG1 upregulation and Wnt signaling pathway activation are integral mechanisms involved in the antagonism between saracatinib and oxaliplatin in HCC The expression of 20,030 genes was compared between wild-type MHCC97L and MHCC97L-Src cells in three independent experiments (Fig. 4a)
Summary
Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Oxaliplatin has commonly been used, the efficacy of oxaliplatin for HCC is poor, due to the presence of both intrinsic and acquired resistance. Oxaliplatin resistance in HCC is a major medical problem, and methods for improvement of the response to this chemotherapeutic are urgently needed [2]. Molecular targeting therapy presents a therapeutic opportunity to impede tumor relapse and reverse drug resistance, while the accurate combined effect is not yet clear in HCC. The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened, and saracatinib treatment induced resistance to oxaliplatin treatment was proved. We evaluated the response of HCC to oxaliplatin and saracatinib in vitro and in vivo, and RNA sequencing revealed that the antagonistic relationship between saracatinib
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